Segmented polyurethane elastomers, which are block copolymers consisting of alternating hard (glassy or semi crystalline) and soft (elastomeric) chain segments, have unique physical and mechanical properties and are known to be biocompatible and blood compatible, due to their hard-segment-soft-segment microphase structure (M. D. Lelah and S L Cooper. Polyurethanes in medicine, CRC Press, Boca Raton, Fla., 1986). For these reasons they are used for a number of biomedical applications.
It is known that aromatic polyurethanes possess better mechanical properties than aliphatic polyurethanes. For many biomedical applications, especially in orthopedic applications, like bone replacement, meniscal reconstruction, or spinal disc replacement, good mechanical properties are required because the forces that orthopedic implants undergo are tremendous. For meniscal reconstruction and meniscal replacement with a degradable porous scaffold, the tear strength of the polymer has found to be important for suturing the implant in place and for the stability of the implant until ingrowth of tissue is complete (De Groot et al. Polymer Bulletin, 1997, 38, 211-218).
The use of aromatic polyurethanes for biomedical applications, especially for applications where degradation of the polymer is required, is undesired. It has been shown that polyurethanes release diamines, which originate from the diisocyanate component in the polymer. The diamines that are released upon degradation for commonly used 4,4′-diphenylmethane diisocyanate and toluene diisocyanate based polyurethanes are 4,4′-diaminodiphenylmethane and toluene diamine, respectively, which are known to be very toxic and carcinogenic (M. Szycher. J. Biomaterial Applications, 1988, 3, 297-402).
De Groot et al. (Polymer Bulletin, 1997, 38, 211-218) used a putrescine based diisocyanate, 1,4-butane diisocyanate, for the preparation of poly(ε-caprolactone) based urethane ureas with excellent mechanical properties, such as a extremely high tear strength. The polyurethanes ureas were made by endcapping a poly(ε-caprolactone) macrodiol with a large excess of 1,4-butane diisocyanate to provide a suitable macrodiisocyanate. After this reaction, the excess diisocyanate was removed and the macrodiisocyanate was chain extended with 1,4-butanediamine.
It is known that polyurethane ureas possess better mechanical properties than polyurethanes, due to the higher melting temperature. This is due to a better packing of the hard segments as a result of bifurcated hydrogen bonding (L. Born et al. Colloid and Polymer Science, 1985, 263, 355). That is the reason why polyurethane ureas are more difficult to process compared to polyurethanes. In addition, polyurethane ureas are more difficult to produce compared to polyurethanes. Due to the high reactivity between diisocyanates and diamines, large amounts of solvents are needed.
C. J. Spaans et al. (Polymer Bulletin, 41, 131-138, 1998) described that polyurethane urea with poly(ε-caprolactone) soft segments and butane diisocyanate/butanediamine hard segments shows a high tensile strength, a high modulus and a high resistance to tearing. However, the polymer processing proved to be difficult. When in stead of a diamine in the chain extension step a diol (1,4-butanediol) was used, a processible polyurethane was obtained but the tear and tensile strengths were far less. Even polyurethanes with longer hard segments had a lower tear strength than the polyurethane ureas. (C. J. Spaans, Biomedical Polyurethanes Based On 1,4-Butanediisocyanate: An Exploratory Study. 2000 PhD Thesis ISBN 90-367-1232-7, chapter 3).
The mechanical properties are especially important when the polymers are intended for use in implants. To this end, the polymers are e.g. processed into porous scaffolds used for, for example, tissue engineering, bone replacement, meniscal reconstruction and meniscal replacement.
Spaans et al. attempted to enhance the mechanical properties of the polyurethanes by synthesising polyurethanes with longer hard segments. A chain extender was synthesised from 1,4-butane diisocyanate (BDI) and 1,4-butanediol (BDO) first, and the resulting BDO.BDI.BDO chain extender was subsequently reacted with the macrodiisocyanate (C. J. Spaans et al., Polymer Bulletin, 41, 131-138, 1998). This method with the BDO.BDI.BDO chain extender is also described in WO9964491, wherein a method for the production of polyurethanes based on co-polyesters of caprolactone and L-lactide is described. The BDO.BDI.BDO or BDI.BDO.BDI.BDO.BDI blocks described in WO9964491 were used as chain extenders for a macrodiisocyanate or macrodiol respectively. When the latter block was used, good results were obtained. However, the synthesis of these longer chain extenders complicates the production method.
A need therefore still existed for segmented polyurethane elastomers that are easy to synthesise, have good mechanical properties and can be processed into, for example, porous scaffolds (foams) for use as implants.
The synthesis of polyurethanes is in the state of the art usually carried out in the presence of a catalyst, such as stannous octoate, dibutyl stannous dilaureate and/or tertiary amines, such as diazabicyclooctane.
A process for the preparation of catalyst free polyurethanes is also described in U.S. Pat. No. 5,374,704. In this process macrodiols such as Desmophen 2000 are reacted with a (cyclo)aliphatic diisocyanate and chain extended with a (cyclo)aliphatic diol. The process is a conventional two-step process wherein the pre-polymer is first reacted with the diisocyanate, and subsequently chain extended with the diol. When an excess diisocyanate was used, the excess was not removed. In the chain extent step a larger amount of chain extender was used resulting in larger hard segment. These hard segments are not uniform, which is related to the synthesis process. The minimum temperature required for the chain extension step in the process described in U.S. Pat. No. 5,374,704 is 100° C. Mechanical properties of the resulting polymers described in U.S. Pat. No. 5,374,704 were not tested and were not compared to prior art polymers that were synthesised with a catalyst.
Spaans (C. J. Spaans, Biomedical Polyurethanes Based On: 1,4-Butanediisocyanate: An Exploratory Study. 2000 PhD Thesis ISBN 90-367-1232-7, chapter 2) synthesised polyurtehanes ureas from a macrodiol (poly ε-caprolactone), a diisocyanate (butane diisocyanate) and a diamine (1,4 butanediamine).
Spaans compared two different methods for the synthesis of the polyurethane ureas. In a first method, the macrodiol was reacted with 2 equivalent diisocyanate, and subsequently chain extended with a diamine. In a second method, the macrodiol was reacted with an excess of diisocyanate to ensure the formation of a diisocyanate endcapped diol. The excess of diiosocyanate was used to ensure the reaction of each macrodiol with two molecules of diisocyanate (and to prevent the formation of macrodiol dimers, trimers etc linked by isocyanate groups). The excess of diisocyanate was removed prior to chain extension with the diamine. The excess of diisocyanate was removed prior to chain extension to prevent the formation of multimers of the chain extender (linked by diisocyanate groups). By this second method, a small size distribution of hard segments formed in the chain extension step is obtained, resulting in improved mechanical properties, compared to the polyurethanes obtained in the first method (or the method disclosed in U.S. Pat. No. 5,374,704, where a narrow size distribution of hard segments cannot be ensured).
For the second method of Spaans, it is essential that all intermediate reaction steps go to completion, i.e. that all —OH groups on the macrodiol molecules are endcapped, especially since the unreacted diisocyanate is removed from the reaction mixture afterwards. Any remaining unreacted —OH group on a macrodiol molecule, will prevent the subsequent formation of a polyurethane in the chain extension step.
In contrast, in the first method of Spaans (and U.S. Pat. No. 5,374,704) unreacted diisocyanate remains in the reaction mixture and may still react with any remaining —H groups during the chain extension step.
With respect to the preparations of porous scaffolds, several techniques are known in the art. Gogolewski and Pennings (Makro. Rapid Com. 1982, 3, 839; Makro. Rapid corn. 1983, 4, 213) used a dipcoat technique, in which a polymer solution is mixed with particulate material. A mandrel is dipped in the polymer solution/particulate, after which the coated mandrel was dipped in a non-solvent for the polymer, which resulted in precipitation of the polymer. Subsequently, the particulate material was washed out. In order to produce porous scaffolds with a reasonable thickness (>1 mm), the method has to be repeated several times, which is a disadvantage.
The preparation of thick porous scaffolds is possible using particulate leaching (e.g. De Groot and Pennings et al., Colloid and Polymer Science, 1990, 268, 1073). The essence to create an open-interconnected-pore structure with this technique is that the particles of the pore forming material have to make contact with each other. This technique has disadvantages. In order to obtain an open interconnected pore structure, large amounts of leaching material are required. This results in high porosity materials with no strength and compression modulus. In addition, it has found to be difficult to leach out all the particulate. The remaining salts in the scaffold can cause cell damage.
Another technique has been described by Aubert et al. to produce low density foams (J. H. Aubert and Clough. Polymer, 1985, 26 2047-2054). Polymer solutions are frozen, after which the solvent is removed by sublimation (freeze-drying). The technique of freeze drying for the removal of the solvent, in stead of precipitation (e.g. Gogolewski and Penning, see above), enables the preparation of thick porous scaffolds. The solid solvent keeps the polymer structure fixated during solvent removal. The morphology of the pores, depends on the phase diagram of the polymer in the particular solvent and the freezing point of the solvent. Pore sizes up to 20 μm are reported, which are too small for tissue engineering applications.
The same technique has also been described as a method to produce biomedical porous polymers (Y. S. Nam and T. G. Park. Biomaterials, 1999; 20, 1783-1790). The resulting porous structures had either pores that were too small (below 30 micrometer) for biomedical applications or were poorly interconnected (interconnection between pores was less than 30 μm).
De Groot et al. (Colloid and Polymer Science, 1990, 268, 1073-1081) combined freeze-drying and particulate leaching. A polymer solution, mixed with particulate material, was frozen. The solvent was removed by sublimation and the NaCl crystals were washed out. The pore structure contained large pores (100-300 μm) due to leaching out of the NaCl crystals and small channel-like pores with diameter<50 μm due to crystallization of the solvent. This technique enables the formation of pores with a specific size. Interconnectivity of the pores is obtained by sublimation of the solvent. By sublimation of the solvent, the polymer structure is stabilized during solvent removal.
A disadvantage of freeze-drying polymer solutions is that it requires solubility of the polymer in solvent that can be freeze-dried. 1,4-Dioxane is the most frequently used solvent to prepare porous materials for tissue engineering. For polymers that are not soluble in the solvents which are applicable for freeze-drying, this technique cannot be used.
A method that does not require solubility in solvents that can be freeze-dried is described in WO9925391. A polymer solution was mixed with particulate material. Then the temperature of the mixture was decreased and after that the mixture was poured into a fluid of a certain temperature that is non-solvent for the polymer and a solvent for the particulate material. A great disadvantage of this method is that the structure is formed during washing and, therefore, the porous structure is not easy to control.
When e.g. meniscus implants are used, it is important that these implants have a high porosity with a high interconnectivity, in order to get a good ingrowth of new tissues, and a high (tear) strength and a high compression modulus to deal with the forces that the implant experiences. To promote ingrowth the interconnection between the pores is preferably more than 30 μm.
Hence, there is also a need for a method for the preparation of porous scaffolds that fulfill these requirements.
Accordingly, the present invention is directed to a method for the preparation of polyurethanes, and a method for producing porous scaffolds (thereof).